Ruthenium(II)-N-alkyl phenothiazine complexes as potential anticancer agents
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2018
Authors
Leskovac, AndrejaPetrović, Sandra
Lazarević-Pašti, Tamara
Krstić, Milena P.
Vasić, Vesna M.
Article (Published version)
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© 2018, SBIC
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In recent years, the search for effective anticancer compounds based on transition metal complexes has been the focus of medical investigations. The synergy between the ruthenium(II) and N-alkylphenothiazine counter-ions (chlorpromazine hydrochloride, thioridazine hydrochloride and trifluoperazine dihydrochloride, respectively) through the formation of three different complexes (1–3) was investigated. We explored whether the selected counter-ions and complexes might affect redox homeostasis and genome integrity of normal human blood cells, and induce an inhibition of Na+/K+-ATPase and AChE at pharmacologically relevant doses. Our results have shown that counter-ions and complexes did not affect the activity of Na+/K+-ATPase, while AChE activity was inhibited in a dose-dependent manner. All investigated compounds disturbed the viability and redox homeostasis of lymphocytes. Complexes 1 and 2 displayed potent cytotoxic and prooxidant action while complex 3 behaved as a weaker genotoxic i...nducer. Still, the tested complexes appeared to be less genotoxic and more cytostatic than the corresponding counter-ions. The effects of selected complexes were also tested in PC12 and U2OS cancer cells with special attention being given to the ability of phenothiazines to affect dopamine D2 receptors. Using the confocal laser scanning microscopy, we observed that all the complexes reduced cell viability. Although all investigated complexes have been bound to the dopamine receptor D2-eGFP, only complex 3 reduced its surface density and increased its lateral mobility in investigated cell lines. Albeit the role of alternative targets for complex 3 cannot be ruled out, its effects should be further examined as potential treatment strategy against cancer cells that overexpress D2.
Keywords:
ruthenium (II)-N-alkyl phenothiazine complexes / cytotoxicity / oxidative stress / dopamine D2 receptorSource:
JBIC Journal of Biological Inorganic Chemistry, 2018, 23, 5, 689-704Funding / projects:
- Studies of enzyme interactions with toxic and pharmacologically active molecules (RS-MESTD-Basic Research (BR or ON)-172023)
- COST Action [MP1302]
DOI: 10.1007/s00775-018-1560-x
ISSN: 0949-8257; 1432-1327
PubMed: 29644470
WoS: 000435951600001
Scopus: 2-s2.0-85049351568
URI
http://link.springer.com/10.1007/s00775-018-1560-xhttps://vinar.vin.bg.ac.rs/handle/123456789/7765
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VinčaTY - JOUR AU - Leskovac, Andreja AU - Petrović, Sandra AU - Lazarević-Pašti, Tamara AU - Krstić, Milena P. AU - Vasić, Vesna M. PY - 2018 UR - http://link.springer.com/10.1007/s00775-018-1560-x UR - https://vinar.vin.bg.ac.rs/handle/123456789/7765 AB - In recent years, the search for effective anticancer compounds based on transition metal complexes has been the focus of medical investigations. The synergy between the ruthenium(II) and N-alkylphenothiazine counter-ions (chlorpromazine hydrochloride, thioridazine hydrochloride and trifluoperazine dihydrochloride, respectively) through the formation of three different complexes (1–3) was investigated. We explored whether the selected counter-ions and complexes might affect redox homeostasis and genome integrity of normal human blood cells, and induce an inhibition of Na+/K+-ATPase and AChE at pharmacologically relevant doses. Our results have shown that counter-ions and complexes did not affect the activity of Na+/K+-ATPase, while AChE activity was inhibited in a dose-dependent manner. All investigated compounds disturbed the viability and redox homeostasis of lymphocytes. Complexes 1 and 2 displayed potent cytotoxic and prooxidant action while complex 3 behaved as a weaker genotoxic inducer. Still, the tested complexes appeared to be less genotoxic and more cytostatic than the corresponding counter-ions. The effects of selected complexes were also tested in PC12 and U2OS cancer cells with special attention being given to the ability of phenothiazines to affect dopamine D2 receptors. Using the confocal laser scanning microscopy, we observed that all the complexes reduced cell viability. Although all investigated complexes have been bound to the dopamine receptor D2-eGFP, only complex 3 reduced its surface density and increased its lateral mobility in investigated cell lines. Albeit the role of alternative targets for complex 3 cannot be ruled out, its effects should be further examined as potential treatment strategy against cancer cells that overexpress D2. T2 - JBIC Journal of Biological Inorganic Chemistry T1 - Ruthenium(II)-N-alkyl phenothiazine complexes as potential anticancer agents VL - 23 IS - 5 SP - 689 EP - 704 DO - 10.1007/s00775-018-1560-x ER -
@article{ author = "Leskovac, Andreja and Petrović, Sandra and Lazarević-Pašti, Tamara and Krstić, Milena P. and Vasić, Vesna M.", year = "2018", abstract = "In recent years, the search for effective anticancer compounds based on transition metal complexes has been the focus of medical investigations. The synergy between the ruthenium(II) and N-alkylphenothiazine counter-ions (chlorpromazine hydrochloride, thioridazine hydrochloride and trifluoperazine dihydrochloride, respectively) through the formation of three different complexes (1–3) was investigated. We explored whether the selected counter-ions and complexes might affect redox homeostasis and genome integrity of normal human blood cells, and induce an inhibition of Na+/K+-ATPase and AChE at pharmacologically relevant doses. Our results have shown that counter-ions and complexes did not affect the activity of Na+/K+-ATPase, while AChE activity was inhibited in a dose-dependent manner. All investigated compounds disturbed the viability and redox homeostasis of lymphocytes. Complexes 1 and 2 displayed potent cytotoxic and prooxidant action while complex 3 behaved as a weaker genotoxic inducer. Still, the tested complexes appeared to be less genotoxic and more cytostatic than the corresponding counter-ions. The effects of selected complexes were also tested in PC12 and U2OS cancer cells with special attention being given to the ability of phenothiazines to affect dopamine D2 receptors. Using the confocal laser scanning microscopy, we observed that all the complexes reduced cell viability. Although all investigated complexes have been bound to the dopamine receptor D2-eGFP, only complex 3 reduced its surface density and increased its lateral mobility in investigated cell lines. Albeit the role of alternative targets for complex 3 cannot be ruled out, its effects should be further examined as potential treatment strategy against cancer cells that overexpress D2.", journal = "JBIC Journal of Biological Inorganic Chemistry", title = "Ruthenium(II)-N-alkyl phenothiazine complexes as potential anticancer agents", volume = "23", number = "5", pages = "689-704", doi = "10.1007/s00775-018-1560-x" }
Leskovac, A., Petrović, S., Lazarević-Pašti, T., Krstić, M. P.,& Vasić, V. M.. (2018). Ruthenium(II)-N-alkyl phenothiazine complexes as potential anticancer agents. in JBIC Journal of Biological Inorganic Chemistry, 23(5), 689-704. https://doi.org/10.1007/s00775-018-1560-x
Leskovac A, Petrović S, Lazarević-Pašti T, Krstić MP, Vasić VM. Ruthenium(II)-N-alkyl phenothiazine complexes as potential anticancer agents. in JBIC Journal of Biological Inorganic Chemistry. 2018;23(5):689-704. doi:10.1007/s00775-018-1560-x .
Leskovac, Andreja, Petrović, Sandra, Lazarević-Pašti, Tamara, Krstić, Milena P., Vasić, Vesna M., "Ruthenium(II)-N-alkyl phenothiazine complexes as potential anticancer agents" in JBIC Journal of Biological Inorganic Chemistry, 23, no. 5 (2018):689-704, https://doi.org/10.1007/s00775-018-1560-x . .